Tolerance and physical dependence are predictable consequences of the chronic administration of morphine and morphine-like opioids. These pharmacological properties of opioids are undesirable for both the opioid addict and the pain patient. In the opioid addict, tolerance to the mood effects of an opioid results in rapid dose escalation. Further, withdrawal is a powerful stimulus, engendering drug seeking behavior. For the pain patient, tolerance to opioid analgesia necessitates dose escalation, which can result in an increase in adverse effects (Inturrisi, C.E. "Opioid Analgesic Therapy in Cancer Pain," Advances in Pain Research and Therapy, (K. M. Foley, J. J. Bonica, and V. Ventafridda, Eds.) pp. 133-154, Raven Press, New York (1990) ("Inturrisi")). The development of physical dependence exposes both the pain patient and the opioid addict to the risk of the withdrawal syndrome if opioid administration is abruptly discontinued or an opioid antagonist is inadvertently administered (Inturrisi). Thus, nonopioid drugs that could attenuate and/or reverse opioid tolerance and physical dependence would be a usefull adjunct in pain management. These same drugs could be used in the opioid addict to assist in opioid detoxification and during maintenance treatment by reducing or eliminating withdrawal symptoms. Furthermore, nonopioid drugs that modulate tolerance and dependence, without altering the analgesia effects of opioids, could provide an important new tool with which to investigate the biochemical and molecular mechanisms of opioid analgesia, craving, tolerance, and physical dependence. Thus, a strong argument can be made for the preclinical pharmacological evaluation of nonopioid modulators of opioid tolerance and/or dependence in both "analgesic" and "drug abuse" model systems.
Recent studies (Trujillo et al., "Inhibition of Morphine Tolerance and Dependence by the NMDA Receptor Antagonist MK-801," Science, 251:85-7 (1991) ("Trujillo"); Marek et al., "Excitatory Amino Acid Antagonists (Kynurenic Acid and MK-801) Attenuate the Development of Morphine Tolerance in the Rat," Brain Res., 547:77-81 (1991); Tiseo et al., "Attenuation and Reversal of Morphine Tolerance by the Competitive N-methyl-D-aspartate Receptor Antagonist, LY274614," J. Pharmacol. Exp. Ther., 264:1090-96 (1993) ("Tiseo I"); Kolesnikov et al., "Blockade of mu and kappa.sub.1 Opioid Analgesic Tolerance by NPC 177442, a Novel NMDA antagonist," Life Sci., 53:1489-94 (1993); Kolesnikov et al., "Blockade of Tolerance to Morphine but not to .kappa. Opioids by a Nitric oxide Synthase Inhibitor," Proc. Natl. Acad. Sci. USA, 90:5162-66 (1993); Tiseo et al., "Modulation of Morphine Tolerance by the Competitive N-methyl-D-aspartate Receptor Antagonist LY274614: Assessment of Opioid Receptor Changes," J. Pharmacol. Exp. Ther., 268:195-201 (1994) ("Tiseo II"); Elliott et al., "The NMDA Receptor Antagonists, LY274614 and MK-801, and the Nitric Oxide Synthase Inhibitor, NG-Nitro-L-arginine, Attenuate Analgesic Tolerance to the Mu-Opioid Morphine but not to Kappa Opioids," Pain, 56:69-75 (1994) ("Elliott I"); Elliott et al., "Dextromethorphan Attenuates and Reverses Analgesic Tolerance to Morphine," Pain, 59:361-368 (1994) ("Elliott II"); Inturrisi, C.E., "NMDA Receptors, Nitric Oxide, and Opioid Tolerance," Reg. Peptides, 54:129-30 (1994) have demonstrated that the excitatory amino acid ("EAA") receptor system and the nitric oxide ("NO") system are involved in morphine tolerance and dependence. Since the 1980s, EAAs including glutamate and aspartate, have been identified as neurotransmitters in the vertebrate central nervous system ("CNS"). An important aspect of one EAA, N-methyl-D-aspartate ("NMDA"), is that it opens a distinctive membrane channel, characterized by voltage dependent Mg.sup.2+ blockade and high permeability to calcium ions. Physiologic increases in intracellular calcium subsequent to receptor activation can initiate a number of metabolic changes in the cell, including a calcium-calmodulin mediated activation of nitric oxide synthase ("NOS") leading to the production of NO (Bredt et al., "Nitric Oxide a Novel Neuronal Messenger," Neuron, 8:3-11 (1992)). Activation of NMDA receptors can also alter the expression of cellular regulatory genes, such as c-fos (Bading et al., "Regulation of Gene Expression in Hippocampal Neurons by Distinct Calcium Signaling Pathways," Science, 260:181-86 (1993); Rasmussen et al., "NMDA Antagonists and Clonidine Block C-fos Expression During Morphine Withdrawal," Synapse, 20:68-74 (1995)). However, large and prolonged increases in intracellular calcium, such as those which can occur from excessive NMDA receptor stimulation, are toxic to the cell. Stimulation of EAA/NMDA receptors may represent the pathophysiologic basis of neuronal degeneration in acute or chronic conditions (Meldrum et al., "Excitatory Amino Acid Neurotoxicity and Neurodegenerative Disease," In Lodge D, Collingridge L (eds), Trends in Pharmacological Sciences: The Pharmacology of Excitatory Amino Acids A Special Report, Cambridge, UK, Elsevier, pp. 54-62 (1991)). Thus, EAA receptor antagonists, especially NMDA receptor antagonists, represent a major area of drug development.
In particular, recent studies have demonstrated that co-administration of NMDA receptor antagonists attenuate or reverse the development of tolerance to the analgesic effects of morphine in rodents (Marek, et al., "Delayed Application of MK-801 Attenuates Development of Morphine Tolerance in the Rat," Brain Res., 548:77-81 (1991) ("Marek"); Trujillo; Tiseo I; Tiseo II, Elliott I; Elliott II). Marek discusses the role of MK-801, an NMDA receptor antagonist or blocker, in reducing morphine dependence in laboratory animals. However, MK-801 has been found to be toxic and is, therefore, unsuitable for pharmaceutical use. NMDA receptor antagonists that are currently available for clinical use include ketamine, dextromethorphan, and memantine. Ketamine's utility is limited, because it is only available for use by injection and commonly produces profound psychotomimetic and other undesirable effects at doses required for analgesic effects. Dextromethorphan's utility is limited, because patients with a genetically determined absence of cytochrome P-4502D6 (the liver drug metabolizing enzyme) cannot tolerate increases in dosage. Dextromethorphan is also subject to drug-drug interactions with commonly used drugs that may affect its efficacy and side effect profile. Further, dextromethorphan is rapidly eliminated form the body, necessitating frequent administration. Memantine, a drug used for movement disorders, is currently under clinical investigation and its therapeutic ratio remains to be determined.
Like morphine, methadone binds preferentially to the mu-type of the opioid receptor (Neil, A., "Affinities of Some Common Opioid Analgesics Towards Four Binding Sites in Mouse Brain," Naunvn-Schmiedeberg's Arch. Pharmacol., 328:24-9 (1984)), and produces behavioral effects similar to morphine in rodents and humans (Olsen, G. D., et al. "Clinical Effects and Pharmacokinetics of Racemic Methadone and its Optional Isomers," Clin. Pharmacol. Ther., 21:147-157 (1976) ("Olsen"); Smits et al., "Some Comparative Effects of Racemic Methadone and Its Optical Isomers in Rodents," Res. Commun. Chem. Pathol Pharmacol., 7:651-662 (1974) ("Smits")). The clinically available and commonly used form of methadone is as the racemic mixture (d,l-methadone). The l-isomer is responsible for the opioid properties, whereas the d-isomer is weak or inactive as an opioid (Horng et al., "The Binding of the Optical Isomers of Methadone, .alpha.-Methadol, A-Acetylmethadol and Their N-demethylated Derivatives to the Opiate Receptors of Rat Brain," Res. Commmun. Chem. Pathol. Pharmacol., 14:621-29 (1976) ("Horng")). d-Methadone does not produce opioid-like locomotor activity in mice (Smits), is inactive following intraventricular administration in rats (Ingoglia et al., "Localization of d- and l-methadone after Intraventricular Injection into Rat Brain," J. Pharmacol. Exp. Ther., 175:84-87 (1970)), and is a 50-fold less potent analgesic in humans than l-methadone (Olsen). Further, l-methadone has a 30-fold greater ability to displace [.sup.3 H]naloxone binding than d-methadone (Horng). Thus, the opioid analgesic properties of dl-methadone are attributed to l-methadone (Olsen). The use of d-methadone has not been investigated.
The present invention is directed to overcoming these deficiencies.